An overview of spinal muscular atrophy (SMA)

SMA is a rare and debilitating autosomal recessive neuromuscular disease characterised by motor neuron degeneration and loss of muscle strength1,2

SMA is estimated to affect 1 in 6000 to 10,000 infants, with a carrier frequency of approximately 1 in 35.3-6
In individuals with SMA, degeneration of motor neurons in the spinal cord results in skeletal muscular atrophy and weakness commonly involving the limbs. The bulbar and respiratory muscles are more variably affected.1,2

The lower motor neurons, located in the spinal cord, are important cells involved in motor function in the central nervous system (CNS).7

Cognitive ability does not appear to be impacted by SMA. Individuals with SMA are often noted at diagnosis to have a bright, alert expression that contrasts with their general weakness.2

Watch the mode of disease video

The genetic deficit underlying SMA is well characterised

The role of the survival motor neuron 1 (SMN1)
gene is to produce SMN protein, a protein essential for motor neuron survival and which is highly expressed in the spinal cord.1,8

In SMA, homozygous mutations or deletions of the SMN1 gene produce a shortage of SMN protein, which causes degeneration of motor neurons in the spinal cord.9,11

Nearly all people, including those with SMA, have a second, virtually duplicate gene to SMN1, known as the survival motor neuron 2 (SMN2) gene12,13

SMN2 gene is nearly identical in genomic sequence to the SMN1 gene, differentiated by just 5 nucleotides9

However, a C-to-T nucleotide change in the SMN2 gene creates an exonic splicing suppressor (ESS) that leads to a skipping of exon 7 during transcription2

This results in the SMN2 gene producing a truncated, non-functional, and rapidly degrading unstable protein2

Approximately 10% of SMN2 transcripts result in full-length SMN protein. This amount is insufficient to sustain survival of spinal motor neurons in the CNS.2

Generally, the number of SMN2 gene copies is inversely related

to the severity of SMA

More than 95% of individuals with SMA retain at least 1 copy of the SMN2 gene

About 80% of individuals with Type I SMA have 1 or 2 copies of the SMN2 gene

About 82% of individuals with Type II SMA have 3 copies of the SMN2 gene

About 96% of individuals with Type III SMA have 3 or 4 copies of the SMN2 gene

The SMN2 gene copy number is related to, but not predictive of, disease severity.

Care decisions should not be made based on copy number alone5,14

In any case of SMA, SMN2 gene copy number is less predictive of prognosis than age of onset and the achievement of functional abilities15

In addition to the SMN2 gene, there is some evidence of other genetic modifiers of disease severity, including levels of the protein Plastin-35

Click here for information about the clinical presentation of individuals with SMA.

SMA requires multidisciplinary medical care, or in some instances, a palliative

approach16

Because the presentation and progression of SMA may vary, comprehensive care often involves the participation of multiple disciplines to manage the symptoms of the disease.16 A typical care team may involve a neurologist, respiratory physician, physiotherapist, orthopaedist and dietitian.16

As SMA progresses, a palliative approach may need to be adopted in order to improve quality of life and relieve stress and discomfort. For individuals with SMA, the use of non-invasive ventilation may help avoid hospitalisation and the need for tracheostomy.16

Researchers are exploring a variety of therapeutic options with the aim of developing treatments for SMA, including:17

SMN2 gene enhancement

Gene therapy for SMA

Muscle protection to prevent/restore the loss of muscle function

Neuroprotection of the motor neurons affected by loss of SMN protein

Because of its role in modulating disease severity, the SMN2 gene is a target for investigational treatments.18

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